Chronic lymphocytic leukemia (CLL) is a heterogeneous group of diseases characterized by different maturation states of the B-cells and T-cells, which are related to the aggressiveness of the disorder. Accordingly, CLL is commonly classified into separate categories, including B-cell chronic lymphocytic leukemia of classical and mixed-types, B-cell and T-cell prolymphocytic leukemia, hairy-cell leukemia and hairy-cell variant, splenic lymphoma with circulating villous lymphocytes, large granular lymphocytic leukemia, adult T-cell leukemia/lymphoma syndrome and leukemic phases of malignant lymphomas of both B-cell and T-cell types.
B-cell chronic lymphocytic leukemia (B-CLL) is characterized by proliferation and accumulation of B-lymphocytes that appear morphologically mature but are biologically immature. B-CLL typically occurs in persons over 50 years of age. This disorder accounts for 30% of leukemias in Western countries, with 10,000 new cases being diagnosed annually in the United States alone. The disorder is characterized by proliferation of biologically immature lymphocytes (lymphocytosis), which typically express low levels of surface immunoglobulins, which upon organ infiltration cause lymph-node enlargement and hepato-splenomegaly. In the advanced stages of the disease, bone marrow occupation by the abnormal lymphocytes causes bone marrow failure, resulting in anemia and thrombocytopenia.
The B-cells in CLL have receptors for mouse erythrocytes, a marker of immature B-cells. An increased number of T-cells has been reported in this disorder with an increase in the number of T-suppressor cells. Typically, an inversion of the T-helper/suppressor ratio results, with increased suppressor T-cells and decreased helper T-cells. The absolute number of natural killer cells may also be increased. In addition, chromosome analysis provides prognostic information about overall survival, in addition to that supplied by clinical data in patients with B-cell CLL.
It has been suggested that certain non-steroidal anti-inflammatory drugs (NSAIDs) may exhibit chemopreventative and anti-neoplastic properties. For example, Piazza et al., Cancer Research 57:2452-2459 (1997), discloses that sulindac (an NSAID that acts as a cyclooxygenase inhibitor) causes regression of and prevents recurrence of colonic adenomas in patients with familial adenomatous polyposis in a manner that appears to be independent of the drug's cyclooxygenase inhibition activity. Although induction of apoptosis was suggested, the actual mechanism of action of this NSAID in the inhibition of cell growth is poorly understood.
The compound etodolac, 1,8-diethyl-1,3,4,9-tetrahydro[3,4-b]-indole-1-acetic acid, falls generally in the class of NSAIDs and is a cyclooxygenase inhibitor. Etodolac is used to treat mild-to-moderate pain, osteoarthritis, and rheumatoid arthritis. Other related indole compounds have also been shown to exhibit similar activity. For example, U.S. Pat. Nos. 3,843,681, 3,939,178, 3,974,179 and 4,686,213 disclose indole derivatives based on the 1,3,4,9-tetra-hydropyrano[3,4-b]-indole-1-acetic acid nucleus that are stated to exhibit anti-inflammatory, analgesic, antibacterial and/or antifungal activity. Similar 1,2,3,4-tetrahydro-4H-carbazole and 2,3,4,9-1H-carbazole compounds and their use as cyclooxygenase-2 (COX-2) inhibitors for antiarthritic, colorectacl cancer and Alzheimer's therapy are also disclosed in U.S. Pat. Nos. 5,776,967, 5,824,699 and 5,830,911.